Herceptin

1
Herceptin (trastuzumab)1 target4 mechanisms
of action
2
HER2 role in breast cancer

• Human epidermal growth factor receptor 2 (HER2)
  is a transmembrane protein and part of the HER
  family of 4 growth factor receptors (HER1 to
  HER4)1
• Overexpression of HER2 and/or amplification of
  the HER2 gene occurs in up to 30 of breast
  cancers1-3
• HER2 positivity is associated with2-4
• aggressive disease
• a high risk of relapse
• poor survival
• HER2 is the only member of the HER family
  acknowledged in guidelines for its prognostic and
  predictive value in breast cancer5
• HER2 is an important therapeutic target

Slamon DJ, et al. Science 1989 244
707712 Slamon DJ, et al. Science 1987 235
177182 Penault-Llorca F, et al. J Clin Oncol
(Meeting Abstracts) 2005 23 69s, abs 764 Press
MF, et al. J Clin Oncol 1997 15 28942904
Goldhirsch A, et al. Ann Oncol 2006 17
17221776
3
Trastuzumab targeting HER2

• Recombinant humanised monoclonal antibody
  directed against the extracellular domain of HER2
• Attacks HER2-positive tumours via 4 distinct
  mechanisms of action
• Activation of antibody-dependent cellular
  cytotoxicity (ADCC)
• Prevention of the formation of p95HER2, a
  truncated and very active form of HER2
• Inhibition of cell proliferation by preventing
  HER2-activated intracellular signalling
• Inhibition of HER2-regulated angiogenesis

Slamon DJ, et al. N Engl J Med 2001 344
783-792 Marty M, et al. J Clin Oncol 2005 23
4265-4274 Baselga J. Oncology 2001 61 (Suppl
2) 14-21 Piccart-Gebhart MJ, et al. N Engl J
Med 2005 353 16591672 Romond EH, et al. N
Engl J Med 2005 353 16731684 Slamon D, et al.
Breast Cancer Res Treat 2005 94 (Suppl 1) S5,
abs 1 Slamon D, et al. Abstract 52 presented at
the 29th SABCS, San Antonio, Texas, USA, 14-17
December 2006 Smith I, et al. Lancet 2007 369
29-36
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1. Trastuzumab mediates ADCC
Once bound to the Fc domain of trastuzumab, the
NK cells release substances
that perforate the tumour cell membrane and
promote cell death
Nahta R, Esteva FJ. Breast Cancer Res 2006 8
215 Clynes RA, et al. Nat Med 2000 6
443-446 Gennari R, et al. Clin Cancer Res 2004
10 5650-5655 Arnould L, et al. Br J Cancer
2006 94 259-267
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2. Trastuzumab preventsformation of p95HER2
Formation of the active p95 fragment, through
proteolytic cleavage of the extracellular domain
of HER2
is prevented by trastuzumab
Molina MA, et al. Cancer Res 2001 61
4744-4749 Nahta R, Esteva FJ. Cancer Lett 2006
232 123-138
6
3. Trastuzumab blocks HER2-activated cell
proliferation
HER2 signalling induces cell proliferation
Trastuzumab interrupts this process
Nahta R, Esteva FJ. Cancer Lett 2006 232
123-138 Fry MJ. Breast Cancer Res 2001 3
304-312 Gershtein ES, et al. Clin Chim Acta
1999 287 59-67 Yakes FM, et al. Cancer Res
2002 62 4132-4141 Longva KE, et al. Int J
Cancer 2005 116 359-367
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4. Trastuzumab inhibits HER2-regulated
angiogenesis
HER2 signalling induces angiogenesis
Trastuzumab inhibits this process
Izumi Y, et al. Nature 2002 416 279-280 Nahta
R, Esteva FJ. Cancer Lett 2006 232 123-138 Wen
XF, et al. Oncogene 2006 25 6986-6996 Klos KS,
et al. Cancer 2003 98 1377-1385
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Trastuzumab 1 target4 mechanisms of action
Prevention of formation of p95HER2
Activation of ADCC
Inhibition of cell proliferation
Inhibition ofHER2-regulated angiogenesis
9
Prescribing information (1)
Herceptin (Trastuzumab, humanised IgG1
monoclonal antibody) Therapeutic indications 1)
Treatment of patients with metastatic breast
cancer whose tumours overexpress HER2 a) as
monotherapy after at least two chemotherapy
regimens for their metastatic disease. b) in
combination with paclitaxel for the treatment of
those patients who have not received chemotherapy
for their metastatic disease and for whom an
anthracycline is not suitable. c) in combination
with docetaxel for the treatment of those
patients who have not received chemotherapy for
their metastatic disease. d) in combination with
an aromatase inhibitor for the treatment of
postmenopausal patients with hormone-receptor
positive metastatic breast cancer, not previously
treated with trastuzumab. 2) Treatment of
patients with HER2 positive early breast cancer
following surgery, chemotherapy (neoadjuvant or
adjuvant) and radiotherapy (if applicable).
Posology and method of administration MBC Weekly
schedule Initial loading dose of 4 mg/kg body
weight, subsequent doses of 2 mg/kg body weight.
EBC 3-weekly schedule Initial loading dose of 8
mg/kg body weight, subsequent doses of 6 mg/kg
body weight. Administration as infusions over
approximately 90 minutes. Contraindications
Patients with known hypersensitivity to
trastuzumab, murine proteins, or to any of the
excipients.
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Prescribing information (2)
Patients with severe dyspnoea at rest due to
complications of advanced malignancy or requiring
supplementary oxygen therapy. Special warnings
and precautions for use The use of Herceptin is
associated with cardiotoxicity. All candidates
for treatment should undergo careful cardiac
monitoring. Serious adverse reactions including
infusion reactions, hypersensitivity,
allergic-like reactions and pulmonary events have
been observed. Herceptin should be avoided during
pregnancy and lactation. Undesirable effects
Related to first infusion chills and/or fever.
Other signs and/or symptoms nausea, vomiting,
pain, rigors, dizziness, rash, asthenia,
diarrhoea, hepatic toxicity. In patients treated
with Herceptin combinations cardiac toxicity,
haematological toxicity, infections. Packaging
Herceptin 150 mg Powder for concentrate for
solution for infusion. References 1. Hudis C. N
Engl J Med 200735739-51. 2. Smith I, et al.
Lancet 200736929-36. 3. Marty M, et al. J Clin
Oncol 2005234265-4274.